Title:
Photostabilization of dibenzoylmethane UV-screening agents with arylalkyl benzoate compounds/amide-based oils and photoprotective compositions comprised thereof
Kind Code:
A1


Abstract:
Topically applicable, photostable compositions with respect to UV radiation contain at least one dibenzoylmethane UV-screening agent and at least one arylalkyl benzoate compound and at least one amide-based oil.



Inventors:
Candau, Didier (Bievres, FR)
Application Number:
11/172902
Publication Date:
01/05/2006
Filing Date:
07/05/2005
Primary Class:
International Classes:
A61K8/49; A61K8/41
View Patent Images:



Primary Examiner:
DODSON, SHELLEY A
Attorney, Agent or Firm:
BUCHANAN, INGERSOLL & ROONEY PC (ALEXANDRIA, VA, US)
Claims:
What is claimed is:

1. A topically applicable, photostable cosmetic/dermatological photoprotective composition, comprising an effective UV-photoprotecting amount of at least one dibenzoylmethane UV-screening agent, and, as a stabilizing admixture therefor, a thus effective amount of at least one arylalkyl benzoate compound and at least one amide-based oil, formulated into a topically applicable, cosmetically/dermatologically acceptable medium.

2. The cosmetic/dermatological composition as defined by claim 1, said at least one dibenzoylmethane UV-screening agent being selected from the group consisting of: 2-methyldibenzoylmethane; 4-methyldibenzoylmethane; 4-isopropyldibenzoylmethane; 4-tert-butyldibenzoylmethane; 2,4-dimethyldibenzoylmethane; 2,5-dimethyldibenzoylmethane; 4,4′-diisopropyldibenzoylmethane; 4,4′-dimethoxydibenzoylmethane; 4-tert-butyl-4′-methoxydibenzoylmethane; 2-methyl-5-isopropyl-4′-methoxydibenzoylmethane; 2-methyl-5-tert-butyl-4′-methoxydibenzoylmethane; 2,4-dimethyl-4′-methoxydibenzoylmethane, and 2,6-dimethyl-4-tert-butyl-4′-methoxydibenzoylmethane.

3. The cosmetic/dermatological composition as defined by claim 1, said at least one dibenzoylmethane UV-screening agent comprising 4-(tert-butyl)-4′-methoxydibenzoylmethane or Butyl Methoxy Dibenzoylmethane.

4. The cosmetic/dermatological composition as defined by claim 1, said at least one arylalkyl benzoate compound having the formula (I) or (II) below: embedded image in which: X is O, S or N; n is an integer ranging from 1 to 10; R1 and R2, which may be identical or different, are each a hydrogen atom, a hydroxyl group, a halogen atom, a linear or branched C1-C4 alkoxy radical, a nitro radical, an amino radical, or a C6H6SO2 radical; R3, R4 and R5, which may be identical or different, are each a radical of formula: embedded image in which n has the same definition indicated above; and R6 is a hydrogen atom, a hydroxyl group, a halogen atom, a linear or branched C1-C4 alkoxy radical, a nitro radical, an amino radical, or a C6H6SO2 radical.

5. The cosmetic/dermatological composition as defined by claim 4, said at least one arylalkyl benzoate compound comprising 2-phenylethyl benzoate of formula: embedded image

6. The cosmetic/dermatological composition as defined by claim 1, said at least one amide-based oil having the formula (III) below: embedded image in which: the radical R1 is an optionally functionalized, aliphatic, cycloaliphatic or cyclic, saturated or unsaturated monovalent hydrocarbon-based radical having from 1 to 30 carbon atoms; the radicals R2, R3 and R4, which may be identical or different, are each hydrogen or optionally functionalized, aliphatic, cycloaliphatic or cyclic, saturated or unsaturated monovalent hydrocarbon-based radicals having from 1 to 30 carbon atoms; r is 0 or 1; q is an integer ranging from 0 to 2; p is 0 or 1; with the proviso that: when p=1, then r is 0 and when p=0, then q=0 and r=1.

7. The cosmetic/dermatological composition as defined by claim 6, wherein formula (III): R1 is a linear or branched C1-C22 alkyl radical, a linear or branched C2-C22 alkenyl radical, or an aryl radical; R2 is a hydrogen atom or a linear or branched C1-C6 alkyl radical; R3 is a hydrogen atom or a linear or branched C1-C6 alkyl radical; and R4 is a linear or branched C1-C10 alkyl radical, a linear or branched C2-C10 alkenyl radical, or a sterol residue.

8. The cosmetic/dermatological composition as defined by claim 7, in which the oil of formula (III) is selected from among those in which the group R1(CO)— is an acyl group of an acid selected from the group consisting of acetic acid, toluic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, linoleic acid, linolenic acid, oleic acid, isostearic acid, 2-ethylhexanoic acid, coconut oil fatty acids and palm kernel oil fatty acids; these acids may also contain a hydroxyl group.

9. The cosmetic/dermatological composition as defined by claim 7, in which the oil of formula (III) is selected from among those in which p is 1 and the moiety —N(R2)CH(R3)(CH2)q(CO)— of the amino acid ester is selected from the group consisting of the following amino acids: glycine, alanine, valine, leucine, isoleucine, serine, threonine, proline, hydroxyproline, β-alanine, N-butyl-β-alanine, aminobutyric acid, aminocaproic acid, sarcosine and N-methyl-β-alanine.

10. The cosmetic/dermatological composition as defined by claim 7, in which the oil of formula (III) is selected from among those in which p is 1 and the moiety of the amino acid esters corresponding to the group OR4 is obtained from alcohols selected from the group consisting of methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, isobutanol, 3-methyl-1-butanol, 2-methyl-1-butanol, pentanol, hexanol, cyclohexanol, octanol, 2-ethylhexanol, decanol, lauryl alcohol, myristyl alcohol, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, oleyl alcohol, behenyl alcohol, jojoba alcohol, 2-hexadecyl alcohol, 2-octyldodecanol and isostearyl alcohol.

11. The cosmetic/dermatological composition as defined by claim 1, said at least one amide-based oil comprising: ethyl N-acetyl-N-butylaminopropionate, having the following formula: embedded image isopropyl N-lauroylsarcosinate of formula: embedded image or N,N-diethyltoluamide of formula: embedded image

12. The cosmetic/dermatological composition as defined by claim 1, said at least one dibenzoylmethane UV-screening agent comprising from 0.01% to 10% by weight thereof.

13. The cosmetic/dermatological composition as defined by claim 1, said at least one amide-based oil comprising from 0.1% to 40% by weight thereof.

14. The cosmetic/dermatological composition as defined by claim 1, further comprising at least one other UV-A-active and/or UV-B-active organic or mineral photoprotective agent that is water-soluble or liposoluble or insoluble in the cosmetic solvents commonly employed.

15. The cosmetic/dermatological composition as defined by claim 14, comprising at least one additional organic photoprotective agent selected from among anthranilates; cinnamic derivatives; salicylic derivatives, camphor derivatives; benzophenone derivatives; β,β-diphenylacrylate derivatives; triazine derivatives; benzotriazole derivatives; benzalmalonate derivatives; benzimidazole derivatives; imidazolines; bis-benzazolyl derivatives; p-aminobenzoic acid (PABA) derivatives; methylenebis(hydroxyphenylbenzotriazole) derivatives; benzoxazole derivatives; screening polymers and screening silicones; α-alkylstyrene derivatives; 4,4-diarylbutadienes, and mixtures thereof.

16. The cosmetic/dermatological composition as defined by claim 15, comprising at least one organic UV-screening agent selected from among the following compounds: Ethylhexyl Methoxycinnamate, Homosalate, Ethylhexyl salicylate, Octocrylene, Phenylbenzimidazolesulfonic acid, Benzophenone-3, Benzophenone-4, Benzophenone-5, n-Hexyl 2-(4-diethylamino-2-hydroxybenzoyl)benzoate, 4-Methylbenzylidenecamphor, Terephthalylidenedicamphorsulfonic acid, Disodium phenyldibenzimidazoletetrasulfonate, Methylenebis(benzotriazolyl)tetramethylbutylphenol, Ethylhexyl Triazone, Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine, Diethylhexyl Butamido Triazone, Drometrizole trisiloxane, Polysilicone-15, 1,1-Dicarboxy(2,2′-dimethylpropyl)-4,4-diphenylbutadiene, 2,4-Bis[5-1(dimethylpropyl)benzoxazol-2-yl(4-phenyl)imino]-6-(2-ethylhexyl)imino-1,3,5-triazine, and mixtures thereof.

17. The cosmetic/dermatological composition as defined by claim 14, comprising at least one additional mineral photoprotective agent which comprises treated or untreated metal oxide pigments or nanopigments.

18. The cosmetic/dermatological composition as defined by claim 17, comprising pigments or nanopigments selected from among titanium oxide, zinc oxide, iron oxide, zirconium oxide and cerium oxide, and mixtures thereof, which are treated or untreated.

19. The cosmetic/dermatological composition as defined by claim 1, further comprising at least one agent for artificially tanning and/or browning the skin.

20. The cosmetic/dermatological composition as defined by claim 1, further comprising at least one adjuvant selected from among fatty substances, organic solvents, ionic or nonionic, hydrophilic or lipophilic thickeners, softeners, humectants, opacifiers, stabilizers, emollients, silicones, anti-foams, fragrances, preservatives, anionic, cationic, nonionic, zwitterionic or amphoteric surfactants, active agents, fillers, polymers, propellants and acidifying or basifying agents.

21. A regime or regimen for cosmetically treating or caring for the skin, lips, nails, hair, eyelashes, eyebrows and/or scalp of an individual in need of such treatment, comprising topically applying thereon, a thus effective amount of the cosmetic/dermatological composition as defined by claim 1.

22. A regime or regimen for photoprotecting the skin, hair, lips and/or scalp against the damaging effects of UV-irradiation, comprising topically applying thereon, a thus effective amount of the cosmetic/dermatological composition as defined by claim 1.

23. A process for enhancing the stability with respect to UV-irradiation of at least one dibenzoylmethane UV-screening agent, comprising formulating therewith a thus effective amount of at least one arylalkyl benzoate compound and at least one amide-based oil.

24. The cosmetic/dermatological composition as defined by claim 1, formulated as an emulsion, a milk, a gel, a cream, a lotion, a powder, a stick, a mousse, or a spray.

Description:

CROSS-REFERENCE TO PRIORITY/PROVISIONAL APPLICATIONS

This application claims priority under 35 U.S.C. § 119 of FR 04/51417, filed Jul. 2, 2004, and of provisional application Ser. No. 60/589,010, filed Jul. 20, 2004, each hereby expressly incorporated by reference and each assigned to the assignee hereof. This application is also a continuation of said '010 provisional.

CROSS-REFERENCE TO COMPANION APPLICATIONS

Copending applications Ser. No. ______ [Attorney Docket No. 016800-695] and Ser. No. ______ [Attorney Docket No. 016800-697], each filed concurrently herewith and each also assigned to the assignee hereof.

BACKGROUND OF THE INVENTION

1. Technical Field of the Invention

The present invention relates to a process for photostabilizing, with respect to UV radiation, at least one dibenzoylmethane UV-screening agent with at least one arylalkyl benzoate compound and at least one oil containing in its structure at least one amide functional unit.

The present invention also relates to novel photoprotective compositions, in particular cosmetic compositions for topical application.

2. Description of Background and/or Related and/or Prior Art

It is known that light radiation with wavelengths of from 280 nm to 400 nm permits tanning of the human epidermis and that light rays with wavelengths more particularly from 280 to 320 nm, known as UV-B rays, cause skin burns and erythema which can harm the development of a natural tan. For these reasons, as well as for aesthetic reasons, there is a constant demand for means of controlling this natural tanning in order thus to control the color of the skin; this UV-B radiation should thus be screened out.

It is also known that UV-A rays, with wavelengths from 320 to 400 nm, which cause tanning of the skin, are liable to induce adverse changes therein, in particular in the case of sensitive skin or skin which is continually exposed to solar radiation. UV-A rays cause in particular a loss of elasticity of the skin and the appearance of wrinkles leading to premature aging of the skin. They promote triggering of the erythemal reaction or amplify this reaction in certain individuals and may even be the cause of phototoxic or photoallergic reactions. Thus, for aesthetic and cosmetic reasons such as the conservation of the skin's natural elasticity, for example, an increasingly large number of individuals wish to control the effect of UV-A rays on their skin. It is thus desirable also to screen out UV-A radiation.

For the purpose of protecting the skin and keratin materials against UV radiation, anti-sun compositions comprising organic screening agents that are active in the UV-A range and in the UV-B range are generally used. The majority of these screening agents are liposoluble.

In this respect, one particularly advantageous family of UV-A screening agents currently consists of dibenzoylmethane derivatives, and in particular 4-tert-butyl-4′-methoxydibenzoylmethane, which have high intrinsic absorbing power. These dibenzoylmethane derivatives, which are products that are now well known per se as screening agents that are active in the UV-A range, are described in particular in FR-A-2,326,405 and FR-A-2,440,933, as well as in EP-A-0,114,607; 4-tert-butyl-4′-methoxydibenzoylmethane is moreover currently marketed under the trademark “Parsol 1789” by Roche Vitamins.

Unfortunately, it has been found that dibenzoylmethane derivatives are products that are relatively sensitive to ultraviolet radiation (especially UV-A), i.e., more specifically, they have an annoying tendency to be degraded more or less quickly under the action of this UV. Thus, this substantial lack of photochemical stability of dibenzoylmethane derivatives towards ultraviolet radiation, to which they are by nature intended to be subjected, does not make it possible to ensure constant protection during prolonged exposure to the sun, and so the user must make repeated applications at regular and close time intervals in order to obtain effective protection of the skin against UV rays.

Dibenzoylmethane derivatives are oil-soluble solid screening agents. Among the oils capable of effectively dissolving these UV-screening agents, alkyl benzoates are known, especially C12/C15 alkyl benzoates, for instance the commercial products Finsolv TN or Witconol APM manufactured and marketed by Witco.

However, the alkyl benzoates known hitherto do not solve the problem of the photostability of dibenzoylmethane derivatives with respect to UV radiation.

SUMMARY OF THE INVENTION

It has now surprisingly been determined that by combining the dibenzoylmethane UV-screening agents mentioned above with an effective amount of an arylalkyl benzoate compound and an oil containing in its structure at least one amide unit, it is possible to improve the photochemical stability (or photostability) of these same dibenzoylmethane sunscreens, in a substantial and noteworthy manner.

This essential discovery forms the basis of the present invention.

Thus, the present invention features a process for improving the stability of at least one dibenzoylmethane UV-screening agent with respect to UV radiation, which comprises combining said at least one dibenzoylmethane sunscreen with at least one arylalkyl benzoate compound and at least one oil containing in its structure at least one amide unit.

The expression “oil containing in its structure at least one amide unit” will be understood throughout the text of the description to mean any compound comprising in its chemical structure at least one amide group (or function) of the type: embedded image
and simultaneously having the following characteristics:

  • a) liquid at 25° C.,
  • b) insoluble or immiscible in water at 25° C.,
  • c) no emulsifying properties.

The present invention also features cosmetic or dermatological compositions for topical application which comprise, formulated into a cosmetically acceptable support:

  • (a) at least one UV-screening agent of the dibenzoylmethane derivative type and
  • (b) at least one arylalkyl benzoate compound and
  • (c) at least one oil containing in its structure at least one amide unit.

Too, the present invention also features the use of an arylalkyl benzoate compound in a cosmetic or dermatological composition comprising at least one dibenzoylmethane UV-screening agent, for the purpose of improving the stability with respect to UV rays of said at least one dibenzoylmethane sunscreen.

Other characteristics, aspects and advantages of the invention will become apparent from the detailed description that follows.

DETAILED DESCRIPTION OF BEST MODE AND SPECIFIC/PREFERRED EMBODIMENTS OF THE INVENTION

Among the dibenzoylmethane UV-screening agents that are especially representative are:

  • 2-methyldibenzoylmethane;
  • 4-methyldibenzoylmethane;
  • 4-isopropyldibenzoylmethane;
  • 4-tert-butyldibenzoylmethane;
  • 2,4-dimethyldibenzoylmethane;
  • 2,5-dimethyldibenzoylmethane;
  • 4,4′-diisopropyldibenzoylmethane;
  • 4,4′-dimethoxydibenzoylmethane;
  • 4-tert-butyl-4′-methoxydibenzoylmethane;
  • 2-methyl-5-isopropyl-4′-methoxydibenzoylmethane;
  • 2-methyl-5-tert-butyl-4′-methoxydibenzoylmethane;
  • 2,4-dimethyl-4′-methoxydibenzoylmethane; and
  • 2,6-dimethyl-4-tert-butyl-4′-methoxydibenzoylmethane.

Among the dibenzoylmethane UV-screening agents mentioned above, 4-isopropyldibenzoylmethane will be used in particular, which is marketed under the name “Eusolex 8020” by Merck, and corresponds to the following formula: embedded image

It is most particularly preferred to use 4-(tert-butyl)-4′-methoxydibenzoylmethane or Butyl Methoxy Dibenzoylmethane, marketed under the trademark “Parsol 1789” by Roche Vitamins; this screening agent corresponds to the following formula: embedded image

The dibenzoylmethane derivative(s) may be present in the compositions in accordance with the invention in contents preferably ranging from 0.01% to 10% by weight and more preferably from 0.1% to 6% by weight relative to the total weight of the composition.

The arylalkyl benzoate compounds in accordance with the invention are preferably selected from those of formula (I) or (II) below: embedded image
in which:

X is O, S or N;

n is an integer ranging from 1 to 10 and more preferably from 2 to 6;

R1 and R2, which may be identical or different, are each a hydrogen atom, a hydroxyl group, a halogen atom (chlorine or fluorine), a linear or branched C1-C4 alkoxy radical (preferably methoxy or ethoxy), a nitro radical, an amino radical, or a C6H6SO2 radical;

R3, R4 and R5, which may be identical or different, are each a radical of formula: embedded image
in which n has the same definition indicated above; and R6 is a hydrogen atom, a hydroxyl group, a halogen atom (for example chlorine of fluorine), a linear or branched C1-C4 alkoxy radical (preferably methoxy or ethoxy), a nitro radical, an amino radical, or a C6H6SO2 radical.

The arylalkyl benzoate compounds in accordance with the invention and the syntheses thereof have long been known in the chemistry literature and especially in PL-55230.

Among the arylalkyl benzoate compounds mentioned above, 2-ethyl phenyl benzoate will be used more particularly embedded image
for instance the commercial product X-Tend 226® marketed by ISP.

The arylalkyl benzoate compounds in accordance with the invention may be present in the compositions in accordance with the invention in contents ranging from 0.1% to 40% by weight and more preferably from 0.1% to 30% by weight relative to the total weight of the composition.

The oil(s) having in their structure at least one amide unit in accordance with the invention is (are) preferably selected from the compounds of formula (III) below: embedded image
in which:

  • the radical R1 is an optionally functionalized, aliphatic, cycloaliphatic or cyclic, saturated or unsaturated monovalent hydrocarbon-based radical containing from 1 to 30 carbon atoms and preferably from 1 to 22 carbon atoms, limits inclusive;
  • the radicals R2, R3 and R4, which may be identical or different, are each hydrogen or optionally functionalized, aliphatic, cycloaliphatic or cyclic, saturated or unsaturated monovalent hydrocarbon-based radicals containing from 1 to 30 carbon atoms and preferably from 1 to 22 carbon atoms, limits inclusive;
  • r is 0 or 1;
  • q is an integer ranging from 0 to 2;
  • p is 0 or 1,
  • with the proviso that:
  • when p=1, then r is 0 and when p=0, then q=0 and r=1.

Examples of saturated aliphatic hydrocarbon-based radicals that may especially be mentioned include linear or branched, substituted or unsubstituted C1-C30 and preferably C1-C22 alkyl radicals, and in particular methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl, pentyl, n-amyl, isoamyl, neopentyl, n-hexyl, n-heptyl, n-octyl, 2-ethylhexyl, tert-octyl, decyl, lauryl and octadecyl radicals.

Examples of saturated cyclic hydrocarbon-based radicals that may especially be mentioned include cyclopentyl and cyclohexyl radicals, which are optionally substituted, in particular with alkyl radicals.

Examples of unsaturated aliphatic hydrocarbon-based radicals that may especially be mentioned include linear or branched, substituted or unsubstituted, C2-C30 and preferably C2-C22 alkenyl or alkynyl radicals, and in particular vinyl, allyl, oleyl and linoleyl radicals.

Examples of unsaturated cyclic hydrocarbon-based radicals that may especially be mentioned in particular include aryl radicals such as phenyl and naphthyl, which are optionally substituted, in particular with alkyls, for instance a tolyl radical, and examples of unsaturated cycloaliphatic radicals that may be mentioned more particularly include benzyl and phenylethyl radicals.

The term “functionalized radicals” means radicals comprising in their chemical structure, either in the main chain or on a secondary chain unit, one or more functional groups especially such as esters, ethers, alcohols, amines, amides and ketones, but preferably esters.

The preferred amide-based oils of formula (II) are selected from those in which:

  • R1 is a linear or branched C1-C22 alkyl radical, a linear or branched C2-C22 alkenyl radical, an aryl radical;
  • R2is a hydrogen atom or a linear or branched C1-C6 alkyl radical;
  • R is a hydrogen atom or a linear or branched C1-C6 alkyl radical; and
  • R4 is a linear or branched C1-C10 alkyl radical or a linear or branched C2-C10 alkenyl radical or a sterol residue.

In formula (III) presented above, the group R1(CO)— is an acyl group of an acid preferably selected from the group formed by acetic acid, toluic acid, capric acid, lauric acid, myristic acid, palmitic acid, stearic acid, behenic acid, linoleic acid, linolenic acid, oleic acid, isostearic acid, 2-ethylhexanoic acid, coconut oil fatty acids and palm kernel oil fatty acids. These acids may also contain a hydroxyl group.

In formula (III), when p is 1, the portion —N(R2)CH(R3)(CH2)q(CO)— of the amino acid ester is preferably selected from those corresponding to the following amino acids:

  • glycine, alanine, valine, leucine, isoleucine, serine, threonine, proline, hydroxyproline, β-alanine, N-butyl-p-alanine, aminobutyric acid, aminocaproic acid, sarcosine or N-methyl-β-alanine.

In formula (III), when p is 1, the portion of the amino acid esters corresponding to the group OR4 may be obtained from alcohols selected from the group formed by methanol, ethanol, propanol, isopropanol, butanol, tert-butanol, isobutanol, 3-methyl-1-butanol, 2-methyl-1-butanol, pentanol, hexanol, cyclohexanol, octanol, 2-ethylhexanol, decanol, lauryl alcohol, myristyl alcohol, cetyl alcohol, cetostearyl alcohol, stearyl alcohol, oleyl alcohol, behenyl alcohol, jojoba alcohol, 2-hexadecyl alcohol, 2-octyldodecanol and isostearyl alcohol.

The oils containing in their structure at least one amide function of formula (III) in accordance with the invention are known per se. Certain of these are especially described with their methods of preparation in EP-1,044,676 and EP-0,928,608 from the company Ajinomoto Co. Others are known in cosmetics, for instance insect repellents such as ethyl N-acetyl-N-butylaminopropionate or N,N-diethyltoluamide.

Among the compounds of formula (III) that are particularly preferred, mention may be made of:

(1) ethyl N-acetyl-N-butylaminopropionate, having the following formula: embedded image
such as the product marketed under the trademark Repellent R3535 by Merck;

(2) isopropyl N-lauroylsarcosinate of formula: embedded image
such as the product marketed under the name Eldew SL-205 by Ajinomoto;

(3) N,N-diethyltoluamide of formula: embedded image
such as the product marketed under the trademark Deet by Showa Denko.

The oil(s) containing in their structure at least one amide function as defined above is (are) present in the compositions according to the invention are in concentrations preferably ranging from 0.1% to 40% by weight and more preferably from 1% to 20% by weight relative to the total weight of the composition.

According to the present invention, the photostabilizing mixture of arylalkyl benzoate compound/amide-based oil will be used in a sufficient amount for obtaining an appreciable and significant improvement in the photostability of the dibenzoylmethane derivative in a given composition. This minimum amount of photostabilizer to be used may vary according to the amount of dibenzoylmethane present at the start in the compound and according to the nature of the cosmetically acceptable support adopted for the composition. It may be determined without any difficulty by means of a standard test for measuring photostability.

The compositions in accordance with the invention may also comprise other additional UV-A-active and/or UV-B-active organic or mineral photoprotective agents that are water-soluble or liposoluble or insoluble in the cosmetic solvents commonly used.

The additional organic photoprotective agents are selected especially from anthranilates; cinnamic derivatives; salicylic derivatives; camphor derivatives; benzophenone derivatives; β,β-diphenylacrylate derivatives; triazine derivatives; benzotriazole derivatives; benzalmalonate derivatives; benzimidazole derivatives; imidazolines; bis-benzazolyl derivatives as described in EP-669,323 and U.S. Pat. No. 2,463,264; p-aminobenzoic acid (PABA) derivatives; methylenebis(hydroxyphenylbenzotriazole) derivatives as described in U.S. Pat. Nos. 5,237,071, 5,166,355, GB-2,303,549, DE-197,26,184 and EP-893,119; benzoxazole derivatives as described in EP-0,832,642, EP-1,027,883, EP-1,300,137 and DE-101,62,844; screening polymers and screening silicones such as those described especially in WO 93/04665; dimers derived from α-alkylstyrene, such as those described in DE-198,55,649; 4,4-diarylbutadienes such as those described in EP-0,967,200, DE-197,46,654, DE-197,55,649, EP-A-1,008,586, EP-1, 133,980 and EP-133,981, and mixtures thereof.

As examples of additional organic photoprotective agents, mention may be made of those denoted hereinbelow under their INCI name:

Para-Aminobenzoic Acid Derivatives:

  • PABA,
  • Ethyl PABA,
  • Ethyl dihydroxypropyl PABA,
  • Ethylhexyl dimethyl PABA marketed in particular under the name “Escalol 507” by ISP,
  • Glyceryl PABA,
  • PEG-25 PABA marketed under the name “Uvinul P25” by BASF.

Salicylic Derivatives:

  • Homosalate marketed under the name “Eusolex HMS” by Rona/EM Industries,
  • Ethylhexyl salicylate marketed under the name “Neo Heliopan OS” by Haarmann and Reimer,
  • Dipropylene glycol salicylate marketed under the name “Dipsal” by Scher,
  • TEA salicylate marketed under the name “Neo Heliopan TS” by Haarmann and Reimer.

Cinnamic Derivatives:

  • Ethylhexyl methoxycinnamate marketed in particular under the trademark “Parsol MCX” by Hoffmann LaRoche,
  • Isopropyl methoxycinnamate,
  • Isoamyl methoxycinnamate marketed under the trademark “Neo Heliopan E 1000” by Haarmann and Reimer,
  • Cinoxate,
  • DEA methoxycinnamate,
  • Diisopropyl methylcinnamate,
  • Glyceryl ethylhexanoate dimethoxycinnamate.

β,β-Diphenylacrylate Derivatives:

  • Octocrylene marketed in particular under the trademark “Uvinul N539” by BASF,
  • Etocrylene marketed in particular under the trademark “Uvinul N35” by BASF.

Benzophenone Derivatives:

  • Benzophenone-1 marketed under the trademark “Uvinul 400” by BASF,
  • Benzophenone-2 marketed under the trademark “Uvinul D50” by BASF,
  • Benzophenone-3 or Oxybenzone marketed under the trademark “Uvinul M40” by BASF,
  • Benzophenone-4 marketed under the trademark “Uvinul MS40” by BASF, Benzophenone-5,
  • Benzophenone-6 marketed under the trademark “Helisorb 11” by Norquay,
  • Benzophenone-8 marketed under the trademark “Spectra-Sorb UV-24” by American Cyanamid,
  • Benzophenone-9 marketed under the trademark “Uvinul DS-49” by BASF, Benzophenone-12
  • n-hexyl 2-(4-diethylamino-2-hydroxybenzoyl)benzoate.

Benzylidenecamphor Derivatives:

  • 3-Benzylidenecamphor manufactured under the name “Mexoryl SD” by Chimex,
  • 4-Methylbenzylidenecamphor marketed under the name “Eusolex 6300” by Merck,
  • Benzylidenecamphorsulfonic acid manufactured under the name “Mexoryl SL” by Chimex,
  • Camphor benzalkonium methosulfate manufactured under the name “Mexoryl SO” by Chimex,
  • Terephthalylidenedicamphorsulfonic acid manufactured under the name “Mexoryl SX” by Chimex,
  • Polyacrylamidomethylbenzylidenecamphor manufactured under the name “Mexoryl SW” by Chimex.

Phenylbenzimidazole Derivatives:

  • Phenylbenzimidazolesulfonic acid marketed in particular under the trademark “Eusolex 232” by Merck,
  • Disodium phenyl dibenzimidazole tetrasulfonate marketed under the trademark “Neo Heliopan AP” by Haarmann and Reimer.

Phenyl Benzotriazole Derivatives:

  • Drometrizole trisiloxane marketed under the name “Silatrizole” by Rhodia Chimie,
  • Methylenebis(benzotriazolyl)tetramethylbutylphenol marketed in solid form under the trademark “MIXXIM BB/100” by Fairmount Chemical, or in micronized form as an aqueous dispersion under the trademark “Tinosorb M” by Ciba Specialty Chemicals.

Triazine Derivatives:

  • Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine marketed under the trademark “Tinosorb S” by Ciba Geigy, Ethylhexyltriazone marketed in particular under the trademark “Uvinul T150” by BASF, Diethylhexylbutamidotriazone marketed under the trademark “Uvasorb HEB” by Sigma 3V,
  • 2,4,6-tris(diisobutyl 4′-aminobenzalmalonate)-s-triazine.

Anthranilic Derivatives:

  • Menthyl anthranilate marketed under the trademark “Neo Heliopan MA” by Haarmann and Reimer.

Imidazoline Derivatives:

  • Ethylhexyldimethoxybenzylidenedioxoimidazoline propionate.

Benzalmalonate Derivatives:

  • Polyorganosiloxane containing benzalmalonate functions, for instance Polysilicone-15, marketed under the trademark “Parsol SLX” by Hoffmann LaRoche

4,4-Diarylbutadiene Derivatives:

  • 1,1-Dicarboxy(2,2′-dimethylpropyl)-4,4-diphenylbutadiene

Benzoxazole Derivatives:

  • 2,4-bis[5-(1-dimethylpropyl)benzoxazol-2-yl(4-phenyl)imino]-6-(2-ethylhexyl)imino-1,3,5-triazine marketed under the name Uvasorb K2A by Sigma 3V
  • and mixtures thereof.

The preferred additional organic photoprotective agents are selected from:

  • Ethylhexyl Methoxycinnamate,
  • Homosalate,
  • Ethylhexyl salicylate,
  • Octocrylene,
  • Phenylbenzimidazolesulfonic acid,
  • Benzophenone-3,
  • Benzophenone-4,
  • Benzophenone-5,
  • n-Hexyl 2-(4-diethylamino-2-hydroxybenzoyl)benzoate,
  • 4-Methylbenzylidenecamphor,
  • Terephthalylidenedicamphorsulfonic acid,
  • Disodium phenyldibenzimidazoletetrasulfonate,
  • Methylenebis(benzotriazolyl)tetramethylbutylphenol,
  • Ethylhexyl Triazone,
  • Bis-Ethylhexyloxyphenol Methoxyphenyl Triazine,
  • Diethylhexyl Butamido Triazone,
  • Drometrizole trisiloxane,
  • Polysilicone-15,
  • 1,1-Dicarboxy(2,2′-dimethylpropyl)-4,4-diphenylbutadiene,
  • 2,4-Bis[5-1(dimethylpropyl)benzoxazol-2-yl(4-phenyl)imino]-6-(2-ethylhexyl)imino-1,3,5-triazine,
  • and mixtures thereof.

The additional mineral photoprotective agents are selected from pigments and even more preferably nanopigments (mean size of the primary particles: generally from 5 nm to 100 nm and preferably from 10 nm to 50 nm) of treated or untreated metal oxides such as, for example, nanopigments of titanium oxide (amorphous or crystallized in rutile and/or anatase form), of iron oxide, of zinc oxide, of zirconium oxide or of cerium oxide.

The treated nanopigments are pigments that have undergone one or more surface treatments of chemical, electronic, mechanochemical and/or mechanical nature with compounds as described, for example, in Cosmetics &Toiletries, February 1990, Vol. 105, pp. 53-64, such as amino acids, beeswax, fatty acids, fatty alcohols, anionic surfactants, lecithins, sodium, potassium, zinc, iron or aluminum salts of fatty acids, metal (titanium or aluminum) alkoxides, polyethylene, silicones, proteins (collagen or elastin), alkanolamines, silicon oxides, metal oxides, sodium hexametaphosphate, alumina or glycerol.

The treated nanopigments may more particularly be titanium oxides treated with:

  • silica and alumina, such as the products “Microtitanium Dioxide MT 500 SA” and “Microtitanium dioxide MT 100 SA” from the company Tayca, and the products “Tioveil Fin”, “Tioveil OP”, “Tioveil MOTG” and “Tioveil IPM” from the company Tioxide,
  • alumina and aluminum stearate, such as the product “Microtitanium Dioxide MT 100 T” from the company Tayca,
  • alumina and aluminum laurate, such as the product “Microtitanium Dioxide MT 100 S” from the company Tayca,
  • iron oxides and iron stearate, such as the product “Microtitanium Dioxide MT 100 F” from the company Tayca,
  • silica, alumina and silicone, such as the products “Microtitanium Dioxide MT 100 SAS”, “Microtitanium Dioxide MT 600 SAS” and “Microtitanium Dioxide MT 500 SAS” from the company Tayca,
  • sodium hexametaphosphate, such as the product “Microtitanium Dioxide MT 150 W” from the company Tayca,
  • octyltrimethoxysilane, such as the product “T-805” from the company Degussa,
  • alumina and stearic acid, such as the product “UVT-M160” from the company Kemira,
  • alumina and glycerol, such as the product “UVT-M212” from the company Kemira,
  • alumina and silicone, such as the product “UVT-M262” from the company Kemira.

Other titanium oxide nanopigments treated with a silicone are preferably TiO2 treated with octyltrimethylsilane and for which the mean size of the elementary particles is from 25 to 40 nm, such as the product marketed under the trademark “T805” by Degussa Silices, TiO2 treated with a polydimethylsiloxane and for which the mean size of the elementary particles is 21 nm, such as the product marketed under the trademark “70250 Cardre UF TiO2SI3” by Cardre, anatase/rutile TiO2 treated with a polydimethylhydrogenosiloxane and for which the mean size of the elementary particles is 25 nm, such as the product marketed under the trademark “Microtitanium Dioxide USP Grade Hydrophobic” by Color Techniques.

The uncoated titanium oxide nanopigments are marketed, for example, by Tayca under the trademarks “Microtitanium Dioxide MT 500 B” or “Microtitanium Dioxide MT 600 B”, by Degussa under the name “P 25”, by Wackher under the name “Oxyde de titane transparent PW”, by Myoshi Kasei under the name “UFTR”, by Tomen under the name “ITS” and by Tioxide under the name “Tioveil AQ”.

The uncoated zinc oxide nanopigments are, for example:

  • those marketed under the name “Z-Cote” by Sunsmart;
  • those marketed under the name “Nanox” by Elementis;
  • those marketed under the name “Nanogard WCD 2025” by Nanophase Technologies.

The coated zinc oxide nanopigments are, for example:

  • those marketed under the name “Zinc Oxide CS-5” by Toshibi (ZnO coated with polymethyihydrogenosiloxane);
  • those marketed under the name “Nanogard Zinc Oxide FN” by Nanophase Technologies (as a 40% dispersion in Finsolv TN, C12-C15 alkyl benzoate);
  • those marketed under the name “Daitopersion ZN-30” and “Daitopersion ZN-50” by Daito (dispersions in cyclopolymethylsiloxane/oxyethylenated polydimethylsiloxane, containing 30% or 50% of nanozinc oxides coated with silica and polymethylhydrogenosiloxane);
  • those marketed under the name “NFD Ultrafine ZNO” by Daikin (ZnO coated with perfluoroalkyl phosphate and copolymer based on perfluoroalkylethyl as a dispersion in cyclopentasiloxane);
  • those marketed under the name “SPD-Z1” by Shin-Etsu (ZnO coated with silicone-grafted acrylic polymer, dispersed in cyclodimethylsiloxane);
  • those marketed under the name “Escalol Z100” by ISP (alumina-treated ZnO dispersed in an ethylhexyl methoxycinnamate/PVP-hexadecene/methicone copolymer mixture);
  • those marketed under the name “Fuji ZNO-SMS-10” by Fuji Pigment (ZnO coated with silica and polymethylsilsesquioxane);
  • those marketed under the name “Nanox Gel TN” by Elementis (ZnO dispersed at a concentration of 55% in C12-C15 alkyl benzoate with hydroxystearic acid polycondensate).

The uncoated cerium oxide nanopigments are marketed under the name “Colloidal Cerium Oxide” by Rhone-Poulenc.

The uncoated iron oxide nanopigments are marketed, for example, by Arnaud under the names “Nanogard WCD 2002 (FE 45B)”, “Nanogard Iron FE 45 BL AQ”, “Nanogard FE 45R AQ” and “Nanogard WCD 2006 (FE 45R)” or by Mitsubishi under the name “TY-220”.

The coated iron oxide nanopigments are marketed, for example, by Arnaud under the names “Nanogard WCD 2008 (FE 45B FN)”, “Nanogard WCD 2009 (FE 45B 556)”, “Nanogard FE 45 BL 345” and “Nanogard FE 45 BL” or by BASF under the name “Transparent Iron Oxide”.

Mention may also be made of mixtures of metal oxides, especially of titanium dioxide and of cerium dioxide, including the silica-coated equal-weight mixture of titanium dioxide and of cerium dioxide, marketed by Ikeda under the name “Sunveil A”, and also the alumina, silica and silicone-coated mixture of titanium dioxide and of zinc dioxide, such as the product “M 261” marketed by Kemira, or the alumina, silica and glycerol-coated mixture of titanium dioxide and of zinc dioxide, such as the product “M 211” marketed by Kemira.

The nanopigments may be introduced into the compositions according to the invention in unmodified form or in the form of pigmentary paste, i.e., as a mixture with a dispersant, as described, for example, in GB-A-2,206,339.

The additional photoprotective agents are generally present in the compositions according to the invention in proportions ranging from 0.01% to 20% by weight relative to the total weight of the composition and preferably ranging from 0.1% to 10% by weight relative to the total weight of the composition.

The compositions according to the invention may also contain agents for artificially tanning and/or browning the skin (self-tanning agents) and more particularly dihydroxyacetone (DHA). They are preferably present in amounts ranging from 0.1% to 10% by weight relative to the total weight of the composition.

The compositions in accordance with the present invention may also comprise standard cosmetic adjuvants selected especially from fatty substances, organic solvents, ionic or nonionic, hydrophilic or lipophilic thickeners, softeners, humectants, opacifiers, stabilizers, emollients, silicones, anti-foams, fragrances, preservatives, anionic, cationic, nonionic, zwitterionic or amphoteric surfactants, active agents, fillers, polymers, propellants, acidifying or basifying agents or any other ingredient usually used in cosmetics and/or dermatology.

The fatty substances may consist of an oil or a wax or mixtures thereof. The term “oil” means a compound that is liquid at room temperature. The term “wax” means a compound that is solid or substantially solid at room temperature and whose melting point is generally greater than 35° C.

Oils that may be mentioned include mineral oils (paraffin); plant oils (sweet almond oil, macadamia oil, grapeseed oil or jojoba oil); synthetic oils, for instance perhydrosqualene, fatty alcohols, fatty acids or fatty esters (for instance the C12-C15 alkyl benzoate marketed under the trademark “Finsolv TN” by Witco, octyl palmitate, isopropyl lanolate and triglycerides, including capric/caprylic acid triglycerides), oxyethylenated or oxypropylenated fatty esters and ethers; silicone oils (cyclomethicone and polydimethylsiloxanes, or PDMS) or fluoro oils, and polyalkylenes.

Waxy compounds that may be mentioned include paraffin, carnauba wax, beeswax and hydrogenated castor oil.

Among the organic solvents that may be mentioned are lower alcohols and polyols. These polyols may be selected from glycols and glycol ethers, for instance ethylene glycol, propylene glycol, butylene glycol, dipropylene glycol or diethylene glycol.

Hydrophilic thickeners that may be mentioned include carboxyvinyl polymers such as the Carbopol products (carbomers) and the Pemulen products (acrylate C10-C30-alkylacrylate copolymer); polyacrylamides, for instance the crosslinked copolymers marketed under the names Sepigel 305 (CTFA name: polyacrylamide/C13-14 isoparaffin/Laureth 7) or Simulgel 600 (CTFA name: acrylamide/sodium acryloyldimethyltaurate copolymer/isohexadecane/polysorbate 80) by SEPPIC; 2-acrylamido-2-methylpropanesulfonic acid polymers and copolymers, which are optionally crosslinked and/or neutralized, for instance the poly(2-acrylamido-2-methylpropanesulfonic acid) marketed by Hoechst under the trademark “Hostacerin AMPS” (CTFA name: ammonium polyacryldimethyltauramide); cellulose-based derivatives such as hydroxyethylcellulose; polysaccharides and especially gums such as xanthan gum; and mixtures thereof.

Lipophilic thickeners that may be mentioned include modified clays such as hectorite and its derivatives, for instance the products marketed under the name bentone.

Among the active agents that may be mentioned are:

  • antipollution agents and/or free-radical scavengers;
  • depigmenting agents and/or propigmenting agents;
  • antiglycation agents;
  • NO-synthase inhibitors;
  • agents for stimulating the synthesis of dermal or epidermal macromolecules and/or for preventing their degradation;
  • agents for stimulating fibroblast proliferation;
  • agents for stimulating keratinocyte proliferation;
  • muscle relaxants;
  • tensioning agents;
  • desquamating agents;
  • moisturizers;
  • anti-inflammatory agents;
  • agents acting on the energy metabolism of cells;
  • insect repellants;
  • substance P or CGRP antagonists.

Needless to say, one skilled in this art will take care to select the optional additional compound(s) mentioned above and/or the amounts thereof such that the advantageous properties intrinsically associated with the compounds in accordance with the invention are not, or are not substantially, adversely affected by the envisaged addition(s).

The compositions according to the invention may be prepared according to techniques that are well known to those skilled in the art, in particular those intended for the preparation of emulsions of oil-in-water or water-in-oil type. They may be in particular in the form of a simple or complex emulsion (O/W, W/O, O/W/O or W/O/W emulsion) such as a cream or a milk, in the form of a gel or a cream-gel, or in the form of a lotion, a powder or a solid tube, and may optionally be packaged as an aerosol and may be in the form of a mousse or a spray.

The compositions according to the invention are preferably in the form of an oil-in-water or water-in-oil emulsion.

The emulsions generally contain at least one emulsifier selected from amphoteric, anionic, cationic and nonionic emulsifiers, which are used alone or as a mixture. The emulsifiers are appropriately selected according to the emulsion to be obtained (W/O or O/W).

As emulsifying surfactants that may be used for the preparation of the W/O emulsions, examples that may be mentioned include sorbitan, glycerol or sugar alkyl esters or ethers; silicone surfactants, for instance dimethicone copolyols, such as the mixture of cyclomethicone and of dimethicone copolyol, marketed under the name “DC 5225 C” by Dow Corning, and alkyldimethicone copolyols such as laurylmethicone copolyol marketed under the name “Dow Corning 5200 Formulation Aid” by Dow Corning; cetyldimethicone copolyol, such as the product marketed under the name Abil EM 90R by Goldschmidt, and the mixture of cetyldimethicone copolyol, of polyglyceryl isostearate (4 mol) and of hexyl laurate, marketed under the name Abil WE O9 by Goldschmidt. One or more co-emulsifiers may also be added thereto, which may be selected advantageously from the group comprising polyol alkyl esters. Polyol alkyl esters that may especially be mentioned include glycerol and/or sorbitan esters, for example polyglyceryl isostearate, such as the product marketed under the name Isolan GI 34 by Goldschmidt, sorbitan isostearate, such as the product marketed under the name Arlacel 987 by ICI, sorbitan glyceryl isostearate, such as the product marketed under the name Arlacel 986 by ICI, and mixtures thereof.

For the O/W emulsions, examples of emulsifiers that may be mentioned include nonionic emulsifiers such as oxyalkylenated (more particularly polyoxyethylenated) fatty acid esters of glycerol; oxyalkylenated fatty acid esters of sorbitan; oxyalkylenated (oxyethylenated and/or oxypropylenated) fatty acid esters; oxyalkylenated (oxyethylenated and/or oxypropylenated) fatty alkyl ethers; sugar esters, for instance sucrose stearate; fatty alkyl ethers of sugars, especially alkylpolyglucosides (APG) such as decylglucoside and laurylglucoside marketed, for example, by Henkel under the respective names Plantaren 2000 and Plantaren 1200, cetostearyl glucoside optionally as a mixture with cetostearyl alcohol, marketed, for example, under the name Montanov 68 by SEPPIC, under the name Tegocare CG90 by Goldschmidt and under the name Emulgade KE3302 by Henkel, and also arachidyl glucoside, for example in the form of a mixture of arachidyl alcohol, behenyl alcohol and arachidyl glucoside, marketed under the name Montanov 202 by SEPPIC. According to one particular embodiment of the invention, the mixture of the alkylpolyglucoside as defined above with the corresponding fatty alcohol may be in the form of a self-emulsifying composition as described, for example, in WO-A-92/06778.

When it is an emulsion, the aqueous phase of this emulsion may comprise a nonionic vesicular dispersion prepared according to known processes (Bangham, Standish and Watkins, J. Mol. Biol., 13, 238 (1965), FR-2,315,991 and FR-2,416,008).

The compositions according to the invention find their application in a large number of treatments, especially cosmetic treatments, of the skin, the lips and the hair, including the scalp, especially for protecting and/or caring for the skin, the lips and/or the hair, and/or for making up the skin and/or the lips.

The present invention also features the use of the compositions according to the invention as defined above for the manufacture of cosmetic products for treating the skin, the lips, the nails, the hair, the eyelashes, the eyebrows and/or the scalp, especially care products and makeup products.

The cosmetic compositions according to the invention may be used, for example, as care products and/or anti-sun products for the face and/or the body, of liquid to semi-liquid consistency, such as milks, more or less rich creams, cream-gels and pastes. They may optionally be packaged as an aerosol and may be in the form of mousses or sprays.

The compositions according to the invention in the form of vaporizable fluid lotions in accordance with the invention are applied to the skin or the hair in the form of fine particles by means of pressurization devices. The devices in accordance with the invention are well known to those skilled in the art and include non-aerosol pumps or “atomizers”, aerosol containers comprising a propellant and also aerosol pumps using compressed air as propellant. The latter pumps are described in U.S. Pat. Nos. 4,077,441 and 4,850,517 (forming an integral part of the content of the description).

The compositions packaged in aerosol form in accordance with the invention generally contain conventional propellants, for instance hydrofluoro compounds, dichlorodifluoromethane, difluoroethane, dimethyl ether, isobutane, n-butane, propane or trichlorofluoromethane. They are preferably present in amounts ranging from 15% to 50% by weight relative to the total weight of the composition.

In order to further illustrate the present invention and the advantages thereof, the following specific examples are given, it being understood that same are intended only as illustrative and in nowise limitative. In said examples to follow, all parts and percentages are given by weight, unless otherwise indicated. The following specific anti-sun formulations were prepared; the amounts are indicated in percentages by weight:

Example 1Example 2
Compositions(invention)(invention)
PHASE A:
Polydimethylsiloxane0.50.5
Preservatives1.01.0
Stearic acid1.51.5
Glyceryl monostearate/PEG stearate mixture1.01.0
(100 EO)
Cetylstearyl glucoside/cetylstearyl alcohol2.02.0
mixture
Cetyl alcohol0.50.5
Butylmethoxydibenzoylmethane2.02.0
2-Phenylethyl benzoate (X-Tend 226 from1010
ISP)
N-Lauroyl isopropyl sarcosinate (Eldew SL-10
205 - Ajinomoto)
Ethyl N-butyl-N-acetylaminopropionate10
(R3535 from Merck)
PHASE B:
Deionized waterqs 100qs 100
Sequestering agent0.10.1
Glycerol5.05.0
Xanthan gum0.20.2
Monocetyl phosphate1.01.0
PHASE C:
Isohexadecane1.01.0
Acrylic acid/stearyl methacrylate copolymer0.20.2
Triethanolamineqsqs

The aqueous phase (Phase B) containing all of its ingredients is heated to 80° C. on a water bath. The fatty phase (Phase A) containing all of its ingredients is heated to 80° C. on a water bath. A is emulsified in B with stirring of rotor-stator type (machine from the company Moritz). Phase C is incorporated and the mixture is allowed to cool to room temperature with moderate stirring. The triethanolamine is introduced so as to adjust the pH to the desired value at the end of manufacture.

Each patent, patent application, publication and literature article/report cited or indicated herein is hereby expressly incorporated by reference.

While the invention has been described in terms of various specific and preferred embodiments, the skilled artisan will appreciate that various modifications, substitutions, omissions, and changes may be made without departing from the spirit thereof. Accordingly, it is intended that the scope of the present invention be limited solely by the scope of the following claims, including equivalents thereof.